The overall goal of this research is to define the cellular and, ultimately, the molecular bases for both currently recognized and yet to be defined primary immunodeficiency diseases, so as to provide the most rational and effective therapies for them. Correlative studies of lymphocyte phenotypes and function in patients with genetically-determined immunodeficiency will provide clues to as yet undiscovered molecular derangements and also permit the discovery of atypical phenotypes resulting from known mutations. Several of our hypotheses follow: Most boys with SCID who have a high percentage of B cells and very low percentages of NK cells and low NK function will prove to have mutations in the gene encoding c, even though a majority will have a negative family history. Girls with this phenotype (or boys with this phenotype who do not have mutations in the gene encoding c) will prove to have Jak3 deficiency. SCID infants who express no c or Jak3 mRNA or protein will have more profound defects in B and NK cell function and will be clinically more severely affected than infants expressing c or Jak3 mRNA and proteins with amino acid substitutions. SCIDs who do not have c or Jak3 mutations will be studied for the presence of other known mutations, such as RAG1 or RAG2 deficiencies (ADA is usually excluded at the initial evaluation) or as yet unknown mutations, such as possible IL-7 or IL7R mutations. Studies of B cell isotype switching and immunoglobulin production with anti-CD40 monoclonal antibody plus IL-4 and other cytokines whose receptors do or do not share the c will contribute to the understanding of the nature of the B cell defect in severely antibody- deficient SCID's, as well as in other types of primary antibody deficiency diseases (such as non-X-linked Hyper IgM). Serial post-transplantation analyses of phenotypes, functions and genetic origins of lymphocytes in SCID recipients of haploidentical T cell-depleted parental marrow stem cells will reveal new information about T, B, and NK cell ontogeny not available in any other human experimental system. During the current reporting period, we performed 20 stem cell transplants in patients with primary immunodeficiency. The creation of human SCID haploidentical bone marrow stem cell chimeras has allowed us a unique opportunity to examine the cellular and molecular bases of human thymic education. We postulate that the neonatal SCID thymus is able to mature normal stem cells to phenotypically and functionally normal T cells more rapidly than thymi from older SCIDs. This information is critical to the question of whether stem cell transplants should be done in utero or in the neonatal period, as the P.I. has already achieved a 92% success rate for stem cell transplants done in the neonatal period. We hypothesize that abnormalities in B and NK cell development post-transplantation are related to the underlying molecular defect leading to SCID, and the development of normal B and/or NK cell function is due to the presence of donor B and/or NK cells or to double parental T cell chimerism. Diminished numbers of CD4+ T cells and an increase in / T cells several years after post- transplantation in some SCIDs are an indication of incomplete or inadequate T cell reconstitution and/or autoimmune reactions and may signal the need for a booster transplant. The studies proposed take advantage of a unique large population of patients with genetically- determined immunodeficiency diseases who are referred to the investigators at this CRC.